This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The research in my group is aimed at understanding molecular basis for biological activity and physical properties of integral membrane receptors, enzymes and ion channels involved in neurotransmission. To achieve our goals, three-dimensional structures are determined primarily by x-ray crystallography and functional properties of target proteins are assessed by structure-based site-directed mutagenesis in combination with biophysical and biochemical techniques including electrophysiology. Specifically, we are focusing on three classes of integral membrane proteins, which play key roles in mediating neuronal activities: NMDA receptors, a ligand-gated cation channel that opens upon binding to glutamate and glycine and mediate excitatory synaptic transmission;LDL receptor related protein (LRP), a lipoprotein receptor that associate with NMDA receptors and regulate the strength of synaptic transmission;and gamma-secretase, an intramembrane cleaving protease (iCLIPs) that mediate regulated intramembrane proteolysis (RIP) of amyloid precursor protein (APP) to regulate the production of amyloid beta, a pathogenic product for Alzheimer's disease.